Systematic mapping of genetic vulnerabilities in head and neck cancer

项目摘要/摘要 大量的突变会导致癌症，但观察到的这些突变的非随机组合 导致转化突出了标志性途径和网络在癌症进展中的重要性。 虽然许多途径与癌症有关，但肿瘤的异质性源于不同的诱变剂， 起源的组织、进展的程度等导致每个病例表现出独特的改变路径子集。 综上所述，癌症类型及其起源的多样性，加上巨大的基因和 肿瘤的表观遗传异质性使靶向癌症治疗的发展复杂化。这个 这个项目的前提是癌症突变汇聚到基因相互作用网络中，而这些网络 汇集所有品种的突变，包括致癌基因突变频率较低的基因和肿瘤 抑制器配置文件。因此，我们假设，通过系统地映射这些网络在细胞系和 在临床相关的患者来源的异种移植(PDX)模型中，癌症治疗的新分子靶点可以是 已确认身份。关注头颈部鳞状细胞癌(HNSCC)，这是一种导致超过 全球每年有25万人死亡，这些目标相应地专注于使用最先进的高吞吐量 通过CRISPR-CAS和耦合单细胞分析绘制上位性图谱，以实现对 分析单个基因和基因对的功能，特别是分析肿瘤异质性的影响。 为此，我们的目标是利用&gt；50 HNSCC细胞株和&gt；50 PDX模型的广泛面板。要启用 在这个庞大的集合中进行筛选，我们将利用重点文库和细胞条形码策略，从而 美国将通过集成的池实验有效地筛选基因和细胞面板。加上严谨的 在临床前模型的体外和体内药物和靶向遗传验证中，我们预计我们整合的 实验和计算框架将导致对潜在肿瘤的前所未有的深入了解 生物学以及临床上可操作的遗传脆弱性的解体，以促进精确度的实践 肿瘤学。

Project Summary/Abstract A vast number of mutations contribute to cancer, but the observed non-random combinations of these leading to transformation highlight the importance of hallmark pathways and networks in cancer progression. While many pathways have been implicated in cancer, tumor heterogeneity stemming from different mutagens, tissue of origin, degree of progression, etc. leads to each case exhibiting a unique subset of altered pathways. Taken together, this diversity among cancer types and their origins, compounded by the huge genetic and epigenetic heterogeneity of tumors has complicated the development of targeted cancer treatments. The premise of this project is that cancer mutations converge into genetic interaction networks, and these networks bring together mutations of all varieties, including genes with low frequency of oncogenic mutations, and tumor suppressor profiles. We thus hypothesize that by systematically mapping these networks in both cell lines and in clinically relevant patient-derived xenograft (PDX) models, new molecular targets for cancer therapy can be identified. Focusing on head and neck squamous cell carcinomas (HNSCC), a disease that results in over 250,000 deaths each year worldwide, the aims correspondingly focus on using state-of-the-art high-throughput epistasis mapping via CRISPR-Cas and coupled single-cell analyses to enable systematic interrogation of the functions of individual genes and gene-pairs while notably also assaying the impact of tumor heterogeneity. Towards this we aim to utilize an extensive panel of >50 HNSCC cell lines and >50 PDX models. To enable screening across this vast collection we will utilize focused libraries and cell barcoding strategies that will allow us to efficiently screen across genes and cell panels via integrated pooled experiments. Coupled with rigorous in vitro and in vivo drug and targeted genetic validations in preclinical models, we anticipate our integrated experimental and computational framework will result in unprecedented insights into the underlying tumor biology as well as unraveling of clinically actionable genetic vulnerabilities to advance the practice of precision oncology.